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Biomedical subjects

A Członkowski

Publications and source records attributed to A Członkowski.

At least 19 recordsLinked to original sources
PubMed2005

Immunization with myelin oligodendrocyte glycoprotein and complete Freund adjuvant partially protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced damage in mouse model of Parkinson's disease.

The concept of neuroprotective immunity identifies a new role of autoimmune cells in the CNS pathology. Specifically, immune cells infiltrating the CNS during an injury may help in a regeneration process and prevent the secondary degeneration of neurons. The objectives of our study were to determine the role of autoimmune and peripheral immune enhancement in neurodegeneration process, and to compare the results between young adult and aging animals. C57Bl mice were immunized with either myelin oligodendrocyte glycoprotein (MOG) 35-55 combined with complete Freund adjuvant (CFA), or CFA alone. Following 6 days, the animals were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to produce a damage of the nigrostriatal dopaminergic system. Although immunization with MOG 35-55 combined with CFA resulted in autoimmune encephalomyelosis, it substantially enhanced neuronal survival after the toxic insult. The immunization with CFA alone was also effective in preventing neuronal cell death, but the magnitude of the neuroprotective effect was smaller. Interestingly, the neuroprotective effect of MOG 35-55 and CFA was more pronounced in aging (i.e. 10-month-old) compared with young (i.e. 2-month-old) mice. Our results indicate that an increased immune activation may be beneficial for neurodegenerative processes following the CNS injury, but the mechanisms of such immune neuroprotection and of age differences need further investigation.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Indomethacin protects against neurodegeneration caused by MPTP intoxication in mice.

The anti-inflammatory agents are postulated to be effective in treating neurodegenerative disorders. In this study, we showed that indomethacin (IND) in the dose of 1 mg/kg protected neurons against toxic damage caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice model of Parkinson's disease. IND also diminished microglial activation and lymphocytic infiltration in the injured areas. These observations suggest that anti-inflammatory properties of IND may play a role in the neuron's protection in this model. However, diminished inflammatory reaction may be secondary to less neuronal damage.

Animals↗
PubMed1999

The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse.

In degenerative disorders of the CNS an immune system involvement in the pathological process is postulated. The MPTP model of Parkinson's disease seem to be a good model for studying an inflammation following toxic neurodegeneration. In this model, microglial and astroglial reactions were previously found around impaired neurons. In the present work we showed an immune reaction, including lymphocytic infiltration of CD4+ and CD8+ T cells in the substantia nigra and striatum and elevated MHC class I and II antigens expression on microglia. Many activated lymphocytes were present, showing increased LFA-1 and CD44 antigen expression. We found also that ICAM-1 expression increased on the endothelium and appeared on microglia in the injured regions. Treatment with dexamethasone inhibited T-cell infiltration and MHC class II expression, lessened the glial reaction, and also diminished neuronal impairment. These findings suggest that an immune mechanism may contribute to the neuronal damage following MPTP administration.

Animals↗
PubMed1999

Phenotyping analysis of peripheral blood leukocytes in patients with multiple sclerosis.

Multiple sclerosis (MS) is a central nervous disease thought to be elicited by an autoimmune process. Many studies in recent years have concentrated on finding the alterations in the peripheral blood immune profile in MS patients that would reflect disease activity. In the present study, we investigated surface antigen expression on lymphocytes and granulocytes from MS patients and control subjects. We have studied 29 patients suffering from relapsing-remitting or relapsing-progressive forms of MS. The disease was diagnosed in all patients at least 12 months before inclusion into the study. All patients had no attack at the study entry date or within a previous month. The control group included 29 age-matched subjects. Phenotyping of peripheral blood leukocytes was carried out with different fluorescence-conjugated murine monoclonal antibodies. The analysis was performed with three-color flow cytometry. The following antigens were determined [cluster of definition (CD)]: leukocyte common antigen (LCA) (B220, T 200, Ly-5), CD45; LPS-R (lipopolysaccharide receptor), CD14; found on all T cells, CD3; LFA-2 (lymphocyte function associated antigen, T 11), CD2; coreceptor for MHC class II molecules, found on helper T cells, CD4; coreceptor for MHC class I molecules, found on suppressor/cytotoxic T cells, CD8; B4, found on all human B cells, CD19; NCAM (neural cell adhesion molecule), CD56; integrin beta2 subunit, associated with CD11a (CD11a/CD18, LFA-1, alphaLbeta2) and CD11b (CD11b/CD18, Mac-1,CR3, alphaMbeta2), CD18; alphaL, alpha subunit of integrin LFA-1 (alphaLbeta2, CD11a/CD18), CD11a; alphaM, alpha subunit of integrin Mac-1 (CR3, alphaMbeta2, CD11b/CD18), CD11b; ICAM-1 (intercellular adhesion molecule), CD54; H-CAM, Hermes antigen, Pgp-1, CD44; AIM (activation inducer molecule), early activation antigen, CD69; T-cell receptor gammadelta, TCR gammadelta. In the MS group, we have found a significant increased expression of CD54 and CD44 antigens on lymphocytes, and higher percentage CD54(+) and CD11a+CD54(+) lymphocytes out of all lymphocytes compared with the control group. We have also found a significant increased expression of CD11a, CD18 and CD54 antigens on granulocytes, and higher percentage CD11b+CD18(+) granulocytes out of all granulocytes in MS patients compared with control. Higher levels of expression of the adhesion molecules may reflect the activation state of leukocytes in MS patients.

Adult↗
PubMed1999

MHC class II positive microglia and lymphocytic infiltration are present in the substantia nigra and striatum in mouse model of Parkinson's disease.

We have studied MHC class II antigen expression and lymphocytic infiltration during dopaminergic neurone degeneration produced by intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). Microglial activation was observed in the striatum and in the substantia nigra (SN) in this model. We noticed a marked increase of MHC class II antigen expression on microglia and T-cell recruitment in these regions after MPTP treatment. B-lymphocytes were not observed. T-cell infiltration predominantly consisted of CD8+ cells at every time point but CD4+ cells were present too. More than a half of the observed lymphocytes showed strong staining of CD44 antigen. Our findings suggest a possible immune system involvement in the pathological process following MPTP intoxication.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1999

Ultrastructural changes in substantia nigra and striatum observed on a mouse model of Parkinson's disease induced by MPTP administration.

The study was carried out on a mouse model of Parkinson's disease induced by the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxin which damages dopaminergic neurons in substantia nigra. Occurrence of dark degenerated neurons was the most prominent ultrastructural change. They were characterized by the progressive condensation of cytoplasm and nuclear chromatin as well as by the light mitochondria and dilated cisternae of Golgi apparatus. Dark degenerated neurons were found particularly often on the 7th day after toxication, however on the last day of the observation, only a few neurons showed the features of dark degeneration. It is likely that degenerative changes led to death in the part of neurons only.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1998

Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

We have studied the reaction of glial cells in mice treated with an intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective neurotoxin of dopaminergic nigrostriatal neurons. Signs of injury to the dopaminergic neurons started on the 1st day after MPTP administration and progressed up to the end of the observation time (21st day). A transient microglial reaction was demonstrated from the 1st until the 14th day in the substantia nigra (SN) and striatum. The cells showed an increase in number and changes in morphology. At the ultrastructural level, signs of phagocytosis and features indicating the secretion of biologically active substances were observed. Astrocytosis followed the microglial reaction by one day and was noticed until the end of the observation time. Interleukin-6 immunoreactivity was observed within microglia and astrocytes in the SN on days 2 and 3. There were no signs of depletion of dopaminergic cells or glial activation after the administration of MPTP simultaneously with pargyline, an inhibitor of monoamine oxidase-B that prevents MPTP neurotoxicity. Our study indicates that microglia and astrocytes are involved in the pathological process in the nigrostriatal system following MPTP administration. MPTP alone is not responsible for glial cell activation but its metabolite MPP+ and/or agents released by injured neurons may participate in this process.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Microglial reaction in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induced Parkinson's disease mice model.

We studied the microglial reaction in mice using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced model for Parkinson's disease (PD). Microglial cells were identified by means of the Griffonia simplicifolia lectin (GSA-I-B4). Dopaminergic neurons were marked by tyrosine hydroxylase antibodies. Microglial activation was demonstrated by an increase in cellular number and changes of morphology (increased lectin staining, larger cell bodies and thicker processes) were seen in the substantia nigra from the 1st to the 14th day and in the striatum from the 1st to the 4th day after intoxication. Depletion of dopaminergic neurons was most pronounced 7 and 14 days following the treatment. The results suggest that microglial activation may be involved in the sequence of pathological changes that lead to dopaminergic neuronal damage after MPTP intoxication.

Animals↗
PubMed1993

Peripheral mechanisms of opioid antinociception in inflammation: involvement of cytokines.

It has been shown previously that opioids induce antinociceptive effects at peripheral sites in the presence of inflammatory processes. Besides being elicited by local injection of opioids, such effects can also be obtained by activation of intrinsic opioid mechanisms, e.g. following stress. In the present study the possible role of cytokines in this mechanism was investigated. Unilateral inflammation of the hindpaw of rats was induced by local injection of Freund's complete adjuvant. Intraplantar injection of tumor necrosis factor alpha (TNF alpha) or interleukin-6 induced a dose-dependent increase in the threshold in the paw pressure test in the inflamed but not in the non-inflamed paw. This increase was prevented by local injection of naloxone and the mu-opioid receptor specific antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) as well as by 3-E7, an universal opioid peptide antibody. In rats pretreated with cyclosporin A to suppress the immune system, the antinociceptive effect of TNF alpha was completely inhibited. In concert with previous studies these data indicate that the tested cytokines release opioid peptides (e.g. beta-endorphin and/or enkephalins) from immune cells of the inflamed tissue which act on opioid receptors present on sensory nerve terminals, resulting in antinociception.

Amino Acid Sequence↗
PubMed1991

Normotensive Wistar rats differ from spontaneously hypertensive and renal hypertensive rats in their cardiovascular responses to opioid agonists.

1. The effects of three opioid receptor agonists on the blood pressure and heart rate of anaesthetized normotensive, spontaneously hypertensive and renal hypertensive rats were measured. 2. Mu agonist morphiceptin i.c.v. induced a pressor response and increase in heart rate in hypertensive rats, but hypotension in normotensive rats. After intravenous (i.v.) injection, morphiceptin produced a hypotensive response in all three groups of rats. 3. In contrast, the delta agonist DTLET i.c.v. decreased blood pressure and heart rate in hypertensive rats, but increased both pressure and beat rate in normotensive rats. After i.v. injections DTLET produced a hypertensive response and increase in heart rate in all groups of rats. 4. Kappa agonist U-50, 488H given i.c.v. induced effects similar to morphiceptin: an increase in blood pressure and heart rate in hypertensive and a decrease in normotensive rats. After i.v. injections U-50, 488H produced decreases in blood pressure and heart rate in all treated groups of rats. 5. Pretreatment with naloxone antagonized the activity of morphiceptin but prevented only the stimulating effect of DTLET in normotensive rats. Cardiovascular actions of U-50, 488H were not blocked by naloxone. 6. The results suggest that opioid agonists exert similar changes in cardiovascular function at central and peripheral sites in both models of experimental hypertension and these effects are different in normotensive rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Kappa-opioid receptor-mediated antinociception in the rat. II. Supraspinal in addition to spinal sites of action.

This study examines whether there is a supraspinal, in addition to spinal, component to the antinociceptive actions against heat and pressure stimuli of kappa-opioid receptor agonists (U-69,593, U50,488H, bremazocine and tifluadom) as compared to mu-opioid receptor agonists (Tyr-D-Ala-Gly-NMe-Gly-ol, fentanyl and morphine) in the rat. The antinociception induced by kappa- and mu-opioids (applied s.c.) was unaffected by systemic quaternary naltrexone (50 mg/kg) revealing that it is mediated in the central nervous system. All kappa- and mu-opioids produced dose-dependent antinociception upon intrathecal application, in each case reversible by naloxone (5 mg/kg s.c.). However, intrathecal application of naloxone could only partially (by ca. 50%) antagonize the antinociception evoked by systemically applied U50,488H and morphine: this suggests sites of action in brain in addition to spinal cord for both mu- and kappa-opioids. Intraventricular application of mu-agonists produced maximal, dose-dependent antinociception. All kappa-agonists were also active in producing dose-dependent antinociception although curves were shallow and maximal antinociception could not be attained. The action of tifluadom was shown to be stereospecific. Naltrexone was 10-fold more potent in blocking morphine as compared to U50,488H whereas nor-binaltorphimine, a preferential kappa-antagonist, was 6-fold more potent against U50,488H than morphine. Indeed, whereas a dose of 0.2 mg/kg of naltrexone reversed mu-agonist actions, this dose was inactive against all kappa-agonists: the actions of these could be antagonized only by 2.0 mg/kg. These data indicate that in addition to kappa-receptors in the spinal cord, kappa-receptors in the brain can mediate antinociception against noxious heat and pressure.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat.

Inoculation of the right hind paw with Mycobacterium butyricum rapidly led to swelling and inflammation. The afflicted limb showed an enhanced sensitivity to noxious pressure (hyperalgesia) and a reduced sensitivity to noxious heat 24 h following treatment. Both naloxone and MR 2266 (which has greater activity at kappa-opioid receptors) further increased the sensitivity to pressure (that is, potentiated the hyperalgesia) but did not affect the response to heat. They did not affect the response of the uninflamed paw. At 1 week, only MR 2266 was effective. At both 24 h and 1 week, the inflamed paw showed pronounced supersensitivity to the antinociceptive action of morphine against noxious pressure. At both 24 h and (to a greater extent) 1 week, a rise in levels of immunoreactive (ir)-dynorphin (DYN) was seen in the ipsilateral dorsal horn of the lumbar spinal cord. There was no alteration in the contralateral dorsal horn or in either ventral horn. Furthermore, levels of ir-met-enkephalin (ME) and ir-leu-enkephalin (LE) were unaffected. There was no difference in the density of mu-, delta- or kappa-binding sites in any part of the lumbar cord, at either 24 h or 1 week, between ipsilateral and contralateral tissue. By 3 and 5 weeks postinoculation, the symptoms had spread to the contralateral hind limb and ir-DYN was elevated in the contralateral dorsal horn and the ipsilateral ventral horn. At 5 weeks, levels of ir-ME and ir-LE also were increased in the ipsilateral and contralateral dorsal horns, but not in the contralateral ventral horn. Furthermore, levels of ir-DYN were increased in the cervico-thoracic spinal cord, and rats displayed adrenal hypertrophy and a rise in plasma levels of ir-beta-endorphin (beta-EP). These data indicate: (1) Peripheral inflammation localized to a single limb selectively modifies levels of ir-DYN in ipsilateral dorsal horn. The effect is specific to DYN as compared to ME and LE. The density of mu-, delta-, or kappa-receptors in the lumbar spinal cord is unmodified. (2) The altered response to opioid agonists and antagonists shown by rats with an inflamed limb may be selective to the injured tissue. (3) Alterations in opioid systems associated with unilateral hind limb inflammation may not be exclusively chronic in nature: they appear very rapidly (within 24 h) of the induction of pain. With time, the contralateral limb becomes affected and, eventually, the effects resemble those seen with generalized polyarthritis.

Animals↗
PubMed1987

An analysis of the 'tolerance' which develops to analgetic electrical stimulation of the midbrain periaqueductal grey in freely moving rats.

Electrical stimulation of the ventral midbrain periaqueductal grey (PAG) elicits an opioidergic antinociception against noxious heat and pressure in freely moving rats. Recurrent stimulation was associated with a gradual decline and eventual loss of this stimulation-produced antinociception (SPA). This could be reinstated by an increase in current intensity and this reinstatement was preventable by naloxone. The current intensity--antinociception (dose--response) curve was shifted to the right in recurrently stimulated rats and parallel to that in naive animals. The loss of SPA upon repetitive simulation did not represent a conditioning phenomenon. Thus, tolerant rats exposed to all cues which accompanied stimulation revealed no (compensatory) hyperalgesic response--but rather a slight antinociception. Further, SPA recovered spontaneously in tolerant rats. Moreover, 'extinction' by repeated exposure to all cues accompanying stimulation did not restore or accelerate the recovery of SPA in tolerant animals. Tolerant rats showed no depletion in midbrain PAG or other CNS or hypophyseal pools of beta-endorphin, Met-enkephalin or dynorphin indicating that a depletion of endogenous opioid peptides does not underlie the tolerance which develops to stimulation. In fact recurrently stimulated rats did not show any of the pronounced effects upon CNS pools of opioid peptides which are seen with long-term stress. Moreover, repetitively stimulated rats revealed no indications of stress as judged by a diversity of stress-sensitive parameters; basal nociceptive threshold, core temperature, ingestive behaviour, body weight, adrenal weight and hypophyseal secretion of beta-endorphin and prolactin. The data offer two major conclusions. Firstly, the gradual loss of analgesia upon recurrent stimulation of the midbrain PAG does not reflect a generalized debilitation or stress and neither a conditioning phenomenon nor a depletion of pools of endogenous opioid peptides. Rather it closely corresponds to the pharmacological definition of tolerance and may reflect a process occurring at the level of the opioid receptor and coupled processes. This finding explains the cross-tolerance which we observe recurrently stimulated rats to display to morphine. Secondly, this SPA is not a form of stress-induced analgesia and rats undergoing recurrent stimulation reveal no indications of stress as judged by biochemical, physiological and behavioural parameters.

Adrenal Glands↗
PubMed1987

Activation of periaqueductal grey pools of beta-endorphin by analgetic electrical stimulation in freely moving rats.

Electrical stimulation of the ventral midbrain periaqueductal grey (PAG) elicited an antinociception (analgesia) in freely moving rats. Stimulated animals displayed a pronounced decrease in levels of immunoreactive (ir)-beta-endorphin (beta-EP) in the midbrain PAG. This depletion was selective in that: animals placed in the chamber and not stimulated revealed neither an analgesia nor an alteration in levels of ir-beta-EP. No change in levels of ir-beta-EP was detectable in other brain regions. Both stimulated rats and rats placed in the chamber and not stimulated revealed a rise in circulating ir-beta-EP: the magnitude of this rise did not, however, differ between these groups. Levels of ir-Met-enkephalin, ir-Leu-enkephalin and ir-dynorphin A were modified neither in the PAG nor in other CNS tissues. The data demonstrate that electrical stimulation of the midbrain PAG selectively influences (presumably activates) pools of beta-EP therein. Together with our finding that destruction of PAG-localized beta-EP neurones to block stimulation-analgesia, the data suggest that an activation of intrinsic pools of beta-EP underlies stimulation-produced analgesia elicited from the PAG in the rat.

Animals↗
PubMed1987

Evidence that mu-opioid receptors mediate midbrain "stimulation-produced analgesia" in the freely moving rat.

Electrical stimulation of the ventral midbrain in freely moving rats led to an antinociception against both noxious heat and noxious pressure. Recurrent stimulation was associated with a progressive loss of the antinociceptive efficacy of stimulation. Rats adapted ("tolerant") to stimulation revealed a significant reduction in the antinociceptive potency of a low dose of the systemically applied selective mu-opioid agonist, morphine. In distinction, the antinociceptive effect of the selective kappa-agonist, trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetam ide (U50488H) was not modified. In the presence of naloxone, delivered subcutaneously via minipumps at a low dose for 7 days, the antinociceptive action of morphine was abolished, whereas that of U50488H was not attenuated: this reflects the selective blockade of mu-receptors. Rats receiving naloxone failed to develop an antinociception upon midbrain electrical stimulation. Removal of the pumps led to a supersensitivity to the antinociceptive effects of morphine but not U50488H. Similarly, midbrain stimulation-produced antinociception was enhanced. These data demonstrate that (1) midbrain stimulation-produced analgesia is selectively cross-tolerant to a mu- as compared to a kappa-agonist; (2) a very low dose of naloxone selective for the mu-receptor blocks midbrain stimulation-produced analgesia, and (3) chronic naloxone treatment leads to a selective supersensitivity to a mu-agonist as compared to a kappa-agonist and an enhancement of midbrain stimulation-produced analgesia. Collectively, the data indicate that a mu-opioid receptor mediates midbrain stimulation-produced analgesia in the rat against both noxious heat and noxious pressure.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗